Method of halogenating hydroxyl group

ABSTRACT

A halogenating agent of the formula (1) and a method of halogenating hydroxyl group                    
     wherein R 1  and R 2  are the same or different and are each ethyl, propyl, isopropyl, butyl, isobutyl or allyl; X is chlorine atom or bromine atom; and Y is chlorine ion, bromine ion, dichlorophosphate ion, dibromophosphate ion, chlorosulfonate ion, bromosulfonate ion, chlorooxalate ion or bromooxalate ion.

This application is a division of application Ser. No. 09/402,863, filedOct. 13, 1999, now U.S. Pat. No. 6,194,567, which is a 371 ofPCT/JP98/05579 filed Dec. 10, 1998.

TECHNICAL FIELD

The invention relates to a novel halogenating agent and method ofhalogenating hydroxyl group.

BACKGROUND ART

The novel halogenating agent and halogenating method of the inventionenable high purity and high yield production of halogenated aromaticcompounds, halogenated heterocyclic compounds and halogenatedcholesterol derivatives, each being useful for an intermediate formedicine and agricultural chemical, and also 7-acylamide-3-halocephemderivative useful for general cephem antibiotics used by oraladministration.

As a method of halogenating hydroxyl group, it has been conventionallyproposed to employ for example dimethyl haloiminium compound anddiphenyl haloiminium compound, as a halogenating agent.

More specifically, Journal of Synthetic Organic Chemistry, 1980, 746discloses a method in which dimethylformamide is reacted with oxalyldichloride to obtain dimethyl chloroiminium compound, and hydroxyl groupbonded to a straight-chain alkyl group is chlorinated by using the abovechloroiminium compound. With this method, a 90% yield is achieved,however, such a high yield is not always obtained. Also, the purity ofthe resulting halogenide is about 80% at the most, and the reaction timeis extremely long, namely, 24 hours.

Journal of the Pharmaceutical Society of Japan 85(6), 544-546 (1965)describes a method in which dimethylformamide is reacted with thionylchloride to form dimethyl chloroiminium compound, and phenolic hydroxylgroup is chlorinated by using this compound. This method, however, hasthe drawbacks that it is not applicable to a compound which has on itsbenzene ring a substituent liable to be chlorinated, except for hydroxylgroup, and that since the reaction system becomes strongly acidiccondition, application is limited to one which can be separated outsideof the system, as a crystal, immediately after the termination of thereaction, thus being impractical.

Dimethyl haloiminium compound is also used in preparingN-acyl-4-chloro-1,2-dihydropyridine which is an intermediate foralkaloid [J. Org. Chem. (1993) 58, 7732-7739]. This method is, however,impractical because the reaction time is markedly long, namely, threedays.

Further, it has been proposed to use dimethyl haloiminium compound inproducing a 3-halogenated cephem derivative which is an intermediate forcephalosporin antibiotic used by oral administration (JP-A-116095/1974).With this method, however, the yield is as low as about 60% because the7-position acyl group is also chlorinated, in addition to the desired3-position hydroxyl group.

In the meantime, it is known a method with which the hydroxyl groupbonded to a straight-chain alkyl group, the hydroxyl group bonded to astraight-chain alkenyl group, and the hydroxyl group of cholesterol, arechlorinated by using diphenyl chloroiminium chloride [Chemistry Letters,pp1173-1174 (1984)]. This method, however, fails to overcome thedrawbacks that the reaction time is long, the purity of the resultinghalogenide is low, and high yield is not ensured. Furthermore, thismethod is unsatisfactory for industrial production because the yielddoes not exceed 90% when chlorinating cholesterol or the compoundscontaining a double bond or ether linkage within the straight-chainmolecules.

An object of the invention is to overcome the drawbacks of long reactiontime, unstable yield, low purity, and the formation of by-productobtained by halogenation of other than the desired hydroxyl group, whichdrawbacks being common to the methods of halogenating hydroxyl group byusing dimethyl haloiminium compound or diphenyl haloiminium compound.

DISCLOSURE OF THE INVENTION

The invention relates to halogenating agents of the following formula(1), and a method of halogenating hydroxyl group

wherein R¹ and R², which may be the same or different, each is ethyl,propyl, isopropyl, butyl, isobutyl or allyl; X is chlorine atom orbromine atom; and Y is chlorine ion, bromine ion, dichlorophosphate ion,dibromophosphate ion, chlorosulfonate ion, bromosulfonate ion,chlorooxalate ion or bromooxalate ion.

In accordance with the invention, compounds obtained by-halogenation ofhydroxyl group can be produced at high yield and high purity in a shortperiod of time.

After the present inventor conducted intensive research to solve theproblems in the prior art, it has been found to overcome a variety ofdrawbacks acknowledged in the case of using dimethyl haloiminiumcompound by conducting halogenation of hydroxyl group by using aspecific dialkylhaloiminium compound, namely, the compound in whichalkyl part has 2 to 4 carbon atoms, thereby enabling to produce thedesired halogenide at high yield and high purity in a short period oftime.

More specifically, when the halogenating agent of the invention is used,only hydroxyl group is selectively halogenated, irrespective of thestructure of a hydroxyl group containing compound and the kind of asubstituent other than hydroxyl group. For example, in the reaction with3-hydroxycephem compound described in JP-A-116095/1974, the acyl groupat the 7-position and lactam part are not halogenated, and only thehydroxyl group at the 3-position is selectively halogenated. Therefore,the desired halogenide can be produced at high yield and high purity,and the reaction time is short.

It has also been found by the inventor that the combined use of adimethyl haloiminium compound and a specific organic sulfur compound canalso overcome the drawbacks of dimethyl haloiminium compound and onlyhydroxyl group is selectively halogenated, thus enabling to produce thedesired halogenide at high yield and high purity in a short period oftime.

Description will be made of the respective groups indicated in thepresent specification.

Examples of halogen atom are chlorine atom and bromine atom.

Examples of C₁-C₄ alkyl group are straight-chain or branched-chain alkylgroups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl and tert-butyl.

Examples of C₂-C₈ alkenyl group are straight-chain or branched-chainalkenyl groups, such as vinyl, propenyl, butenyl, pentenyl, hexenyl,isopropenyl, isobutenyl, isopentenyl, octenyl and isoprenyl.

Examples of monocyclic or polycyclic aromatic hydrocarbon group arephenyl group, naphthalene group and anthracene group. Examples ofmonocyclic or polycyclic heterocyclic hydrocarbon group are furyl group,pyrrolyl group, thienyl group, oxazolyl group, imidazolyl group,thiazolyl group, pyridyl group, pyrazyl group, pyridazyl group,morpholinyl group, quinolyl group, isoquinolyl group, indole group,indolizyl group, penicillin residue and cephalosporin residue. Examplesof steroid residue are androsterone residue, testosterone residue andcholesterol residue.

Examples of C_(1-C) ₅ alkyl group are straight-chain, branched-chain orcyclic alkyl groups, such as methyl, ethyl, propyl, butyl, isopropyl,isobutyl, tert-butyl, hexyl, cyclohexyl and pentadecanyl.

Examples of substituted oxycarbonyl group are bromobutoxycarbonyl,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,benzyloxycarbonyl and allyloxycarbonyl.

Examples of acyl group are formyl, acetyl, propionyl, butyryl, valeryl,benzoyl, toluoyl and naphthoyl.

Exemplary of the protected amino group are amido groups such asphenoxyacetamido, p-methylphenoxyacetamido, p-methoxyphenoxyacetamido,p-chlorophenoxyacetamido, p-bromophenoxyacetamido, phenylacetamido,p-methylphenylacetamido, p-methoxyphenylacetamido,p-chlorophenylacetamido, p-bromophenylacetamido,phenylmonochloroacetamido, phenyldichloroacetamido,phenylhydroxyacetamido, thienylacetamido, phenylacetoxyacetamido,α-oxophenylacetamido, benzamido, p-methylbenzamido, p-methoxybenzamido,p-chlorobenzamido, p-bromobenzamido, phenylglycylamido,phenylglycylamido having protected amino, p-hydroxyphenylglycylamido,p-hydroxyphenylglycylamido having protected amino and/or protectedhydroxyl, etc.; imido groups such as phthalimido, nitrophthalimido,etc., in addition to the groups disclosed in Theodora W. Greene, 1981,“Protective Groups in Organic Synthesis” (hereinafter referred to merelyas the “literature”), Chap. 7 (pp. 218˜287). Examples of protectivegroups for the amino of phenylglycylamido group andp-hydroxyphenylglycylamido group are those disclosed in the literature,Chap. 7 (pp. 218˜287). Examples of protective groups for the hydroxyl ofp-hydroxyphenylglycylamido group are those disclosed in the literature,Chap. 2 (pp. 10˜72).

Further, also are included groups of the formula (A)

wherein Ri and Rj are same or different and each a hydrogen atom, C₁-C₁₅alkyl group, aromatic hydrocarbon group or heterocyclic hydrocarbongroup, or may bond together to form a cyclic group.

Examples of C₁-C₁₅ alkyl group, aromatic hydrocarbon group andheterocyclic hydrocarbon group are the same as given above. Examples ofthe aforesaid cyclic group are C₄-C₈ cycloalkyl group (e.g., cyclobutyl,cyclohexyl, cyclooctyl, etc), including carbon bonded to N. and aromaticgroups (e.g., phenyl, tolyl, naphthyl, etc.)

Examples of lower alkoxy group are straight-chain or branched-chainC₁-C₄ alkoxy group, such as methoxy, ethoxy, n-propoxy, isopropoxy,sec-butoxy and tert-butoxy. Examples of cyclic amino protecting groupare phthaloyl group and nitrophthaloyl group. Examples of the protectivegroup for carboxylic acid are allyl group, benzyl group, p-methoxybenzylgroup, p-nitrobenzyl group, diphenylmethyl group, trichloromethyl group,trichloroethyl group and tert-butyl group, in addition to a variety ofgroups as described in the fifth chapter of the aforesaid literature(pages 152-192).

In the invention, the dialkyl haloiminium compounds of the formula (1)are used as a halogenating agent for hydroxyl group. Examples of thedialkyl haloiminium compound are diethyl haloiminium compound,diisopropyl haloiminium compound, dibutyl haloiminium compound, diallylhaloiminium compound, methylethyl haloiminium compound, ethylpropylhaloiminium compound, ethylbutyl haloiminium compound and ethylpentylbaloiminium compound. Of these, preferred is dialkyl haloiminiumcompound in which R¹ and R² are the same group, and particularlypreferred is diethyl haloiminium compound. The dialkyl haloiminiumcompounds may be used singly or in a combination of at least two ofthem.

The dialkyl haloiminium compounds or diallyl haloiminium compounds ofthe formula (1) (hereinafter both are simply referred to as dialkylhaloiminium compounds), can be produced, for example, by allowingdialkylformamide or diallylformamide of the following formula to reactwith a halogenating agent in an organic solvent

wherein R¹ and R² are the same or different and are each same as givenabove.

The organic solvent used herein is not limited specifically insofar asit does not cause adverse effect on the reaction between thedialkylformamide or diallylformamide and the halogenating agent. Thereare, for example, lower alkyl esters of lower carboxylic acid, such asmethyl formate, ethyl formate, propyl formate, butyl formate, methylacetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionateand ethyl propionate; ketones such as acetone, methyl ethyl ketone,methyl propyl ketone, methyl butyl ketone, methyl isobutyl ketone anddiethyl ketone; ethers such as diethyl ether, ethyl propyl ether, ethylbutyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methylcellosolve and dimethoxyethane; cyclic ethers such as tetrahydrofuran,dioxane and dioxolane; nitriles such as acetonitrile, propionitrile,butyronitrile, isobutyronitrile and valeronitrile; aromatic hydrocarbonssuch as benzene, toluene, xylene, chlorobenzene and anisole; halogenatedhydrocarbons such as dichloromethane, chloroform, dichloroethane,trichloroethane, dibromoethane, propylene dichloride and carbontetrachloride; aliphatic hydrocarbons such as pentane, hexane, heptaneand octane; and cycloalkanes such as cyclopetane, cyclohexane,cycloheptane and cyclooctane. They may be used singly or in acombination of at least two of them. If desired, these organic solventsmay be previously dehydrated prior to use by molecular sieves, forexample. Although the amount of organic solvent is not limitedspecifically, it is usually about 1 to 100 liters, preferably about 5 to50 liters, per 1 kg of the dialkylformamide or diallylformamide.

As a halogenating agent, any one known in the art can be used. Thereare, for example, phosgene, oxalyl dichloride, thionyl chloride,phosphorus pentachloride, phosphorous trichloride, phosphorusoxychloride, carbonyl dibromide, oxalyl bromide, thionyl bromide,phosphorous bromide and phosphorus oxybromide. The halogenating agentscan be used singly or in a combination of at least two of them. Althoughthe amount of halogenating agent is not specifically limited, it isusually 0.5 to 10 equivalents to dialkyl formamide or diallyl formamide.If necessary, the halogenating agent may be further added until thedialkyl formamide or diallyl formamide is exhausted.

The above reaction is usually conducted at temperatures of about −78 to60° C., preferably about 0 to 30° C., and the reaction is usuallycompleted in about 0.5 to 20 hours, preferably about 0.5 to 8 hours.After the termination of the reaction, the reaction mixture is purifiedby the usual means such as concentration, thereby isolating thehalogenating agent of the invention (dialkyl haloiminium compound).Alternatively, the reaction mixture containing the halogenating agent ofthe invention can be directly used, without purification, for thehalogenating reaction of hydroxyl group.

A method of halogenating hydroxyl group according to the invention willbe described. In the invention, halogenides of the following formula (3)(hereinafter referred to as “halogenide (3)”) are produced by reactingat least one of the halogenating agents of the formula (1) (hereinafterreferred to as “halogenating agent (1)”) with a hydroxyl groupcontaining compound of the following formula (2) (hereinafter referredto as “hydroxyl containing compound (2)”) in an organic solvent

A-OH  (2)

wherein A is a straight-chain or branched-chain alkyl group which may besubstituted, a straight-chain or branched-chain alkenyl, group which maybe substituted, a monocyclic or polycyclic aromatic residue which may besubstituted, a steroid residue, or a monocyclic or polycyclicheterocyclic residue which may be substituted

A-X  (3)

wherein A and X are the same as above.

The hydroxyl group containing compound is not specifically limited, andany organic compounds which has a hydroxyl group in the molecule can beused. There are, for example, the following compounds (5) through (11).Examples of substituent are aryl group and lower alkoxycarbonyl group.Examples of the lower alkoxy group of the lower alkoxycarbonyl group arealkoxy group having 1 to 4 carbon atoms.

Compound (5)

Straight-chain or branched-chain alkyl alcohol in which alkyl part has 1to 15 carbon atoms and may be substituted.

Compound (6)

Straight-chain or branched-chain alkenyl alcohol in which alkenyl parthas 2 to 8 carbon atoms and may be substituted.

Compound (7)

3β-cholesterol

Compound (8)

Compounds of the formula (8):

wherein R⁵ to R⁸ are the same or different and are each hydrogen atom,C₁-C₄ lower alkyl group, nitro group, hydroxyl group, carboxyl group, orsubstituted oxycarbonyl group.

Compound (9)

Compounds of the formulas (9a) to (9c):

wherein R⁹ is a straight-chain or branched-chain C₁-C₁₅ alkyl group, astraight-chain or branched-chain C₂-C₈ alkenyl group, cyclohexyl group,or phenyl group; and Ra is hydrogen atom or a substituted oxycarbonylgroup.

Compound (10)

Compounds of the formula (10):

wherein R¹⁰ is hydrogen atom, amino group, or a protected amino group;R¹¹ is hydrogen atom or lower alkoxy group, alternatively, R¹⁰ and R¹¹may be bonded with each other to form a cyclic amino protecting group;and R¹² is hydrogen atom or carboxylic acid protecting group.

Compound (11)

Compounds of the formula (11):

wherein R¹³ to R¹⁶ are the same or different and are each hydrogen atom,C₁-C₄ lower alkyl group, nitro group, hydroxyl group, carboxyl group, ora substituted oxycarbonyl group; and n is 1 or 2.

Of these, Compounds (5) to (10) are preferred, Compounds (7) to (10) aremore preferred, Compounds (9) and (10) are most preferred, and Compound(10) is the best.

As an organic solvent, those which are used in producing thehalogenating agent (1) of the invention (the above-mentioned ones) canbe used. It is also possible to use amides containingdimethylacetoamide, dimethylimidazolidinone and a cyclic amide such asN-methyl-2-pyrrolidone. They can be used solely or in a combination ofat least two of them. The amount of organic solvent is not specificallylimited and can be selected appropriately from a wide range. It is,however, usually about 1 to 200 liters, preferably about 5 to 20 liters,per 1 kg of the hydroxyl group containing compound (2).

The amount of the halogenating agent (1) is not specifically limited andcan be selected suitably from a wide range. It is, however, usually 0.1to 10 equivalents, preferably 0.5 to 2.0 equivalents, to the hydroxylgroup containing compound (2). The halogenating compound (1) may beadded, as required, until the hydroxyl group containing compound (2) inthe reaction system is exhausted.

The above reaction is conducted with or without stirring, usually attemperatures of about −78 to 60° C., preferably about 0 to 30° C., andthe reaction is usually terminated in about 0.5 to 20 hours, preferablyabout 0.5 to 8 hours. If necessary, the reaction can also be conductedin a sealed container or in the presence of an inert gas, e.g., nitrogengas. The resulting halogenide (3) is easily isolated by the usualpurification operation, such as concentration, distillation,chromatography and crystallization.

In another feature of the invention, the halogenide (3) can be producedby allowing the hydroxyl group containing compound (2) to react with atleast one kind selected from the group consisting of the halogenatingagents of the formula (1) and those of the formula (4) (hereinafterreferred to as “halogenating agent (4)”), and at least one kind selectedfrom the group consisting of lower alkyl sulfone, lower alkenyl sulfone,aryl sulfone and heterocyclic sulfone, in an organic solvent at the sametime

wherein R³ and R⁵ are methyl or phenyl; and X and Y are the same asabove.

This reaction is particularly effective for the halogenation of Compound(10).

The kind and amount of the organic solvent used herein, the amount ofthe halogenating agent, and the reaction conditions such as the reactiontemperature and time, may be the same as in the case where thehalogenide (3) is produced by using the halogenating agent (1) alone.

Examples of the lower alkyl sulfone, lower alkeny sulfone, aryl sulfoneand heterocyclic sulfone (unless otherwise stated, hereinafter referredto as “sulfones”) are dimethyl sulfone,.diethyl sulfone, dipropylsulfone, diisopropyl sulfone, dibutyl sulfone, diisobutyl sulfone,methylethyl sulfone, methylpropyl sulfone, methylbutyl sulfone,ethylpropyl sulfone, ethylbutyl sulfone, divinyl sulfone, dipropenylsulfone, vinylpropenyl sulfone, diphenyl sulfone, ditoluyl sulfone anddipyridyl sulfone. Solfones can be used solely or in a combination of atleast two of them. The amount of solfones is not specifically limitedand can be suitably selected from a wide range. It is, however, usuallyfrom about 0.1 to 20 mole %, preferably about 3 to 10 mole %, to thehydroxyl group containing compound (2).

In another aspect of the invention, there are provided halogenides bythat, using dialkylformamide or diallylformamide itself as an organicsolvent, a known halogenating agent is reacted therewith to generate thehalogenating agent (1) and/or halogenating agent (4) of the inventionwithin the reaction system, and the hydroxyl group containing compound(2) is then added into the reaction system. When only the halogenatingagent (4) is generated in the reaction system, it is necessary to addsulfones. When the halogenating agent (1) coexists, solfones may beoptionally added. In this case, the reaction conditions, such as theamount of the dialkylformamide or diallylformamide, the amount of thehalogenating agent (1) and /or halogenating agent (4), the kind andamount of sulfones, and the reaction temperature and time, may be thesame as stated earlier. If necessary, the reaction can also be conductedin a sealed container or in the presence of an inert gas, e.g., nitrogengas. The resulting halogenide (3) is easily isolated by the usualpurification operation, such as concentration, distillation,chromatography and crystallization.

BEST MODE OF CARRYING OUT THE INVENTION

The following Preparation Examples (the preparation of the halogenatingagent (1) or the halogenating agent (4)), Examples and ComparativeExamples are being supplied to further define the present invention.

PREPARATION EXAMPLE 1

The atmosphere of a 300-ml four-necked flask equipped with athermometer, a calcium chloride tube and a stirrer was replaced withargon gas, and 50 ml of methylene chloride and 4.3 g ofN,N-diethylformamide were placed in the flask and then stirred with icecooling. Then, 5.23 ml of oxalyl dichloride was added.by a syringe andfurther stirred with ice cooling for one hour. The reaction mixture wassubjected to vacuum concentration and then crystallization with 50 ml ofethyl ether, to prepare 6.4 g of N,N-diethylchloroiminium chloride (1a).

¹H NMR(CDCl₃) δ1.45 (t, J=7.4 Hz, 6H), 4.23 (brs, 4H), 10.94 (s, 1H)

PREPARATION EXAMPLE 2

The procedure was conducted in the same manner as in Preparation Example1 except that 6.0 g of N,N-di-n-propylformamide was used in place of 4.3g of N,N-diethylformamide, to prepare 8.8 g ofN,N-di-n-propylchloroiminium chloride (1b).

¹H NMR(CDCl₃) δ1.39 (t, J=7.4 Hz, 6H), 3.75 (m, 2H), 3.95 (m, 2H), 4.23(t, J=7.4 Hz, 2H), 4.44 (t, J=7.4 Hz, 2H), 10.71 (s, 1H)

PREPARATION EXAMPLE 3

The procedure was conducted in the same manner as in Preparation Example1 except that 6.1 g of N,N-diisopropylformamide was used in place of 4.3g of N,N-diethylformamide, to prepare 8.7 g ofN,N-diisopropylchloroiminium chloride (1c).

¹H NMR(CDCl₃) δ1.41 (m, 12H), 3.81 (m, 1H), 4.20 (m, 1H), 10.93 (s, 1H)

PREPARATION EXAMPLE 4

The procedure was conducted in the same manner as in Preparation Example1 except that 7.6 g of N,N-di-n-butylformamide was used in place of 4.3g of N,N-diethylformamide, to obtain 11.3 g ofN,N-di-n-butylchloroiminium chloride (1d).

¹H NMR(CDCl₃) δ1.37 (t, J=7.4 Hz, 6H), 3.89 (m, 8H) 4.14 (t, J=7.4 Hz,4H), 10.75 (s, 1H)

PREPARATION EXAMPLE 5

The procedure was conducted in the same manner as in Preparation Example1 except that 5.7 g of N,N-di-allylformamide was used in place of 4.3 gof N,N-diethylformamide, to prepare 8.5 g of N,N-di-allylchloroiminiumchloride (1e).

¹H NMR(CDCl₃) δ3.56 (d, J=7.5 Hz, 4H), 5.355 (m, 4H), 6.10 (m, 2H),10.94 (s, 1H)

PREPARATION EXAMPLE 6

Into a dried 50-ml eggplant type flask was placed 35 ml of dehydrateddiethylformamide and 4.2 g of phosphorus oxychloride was then addedthereto at room temperature. The mixture was stirred at 30° C. for onehour, to prepare a solution of diethyl chloroiminium chloride compoundin diethylformamide.

PREPARATION EXAMPLE 7

The procedure was conducted in the same manner as in Preparation Example6 except that dehydrated dimethylformamide was used in place of thedehydrated diethylformamide, to prepare a solution of dimethylchloroiminium chloride compound in dimethylformamide.

Example 1

Preparation of Diphenylmethyl(6R, 7R)-7-phenylacetamide-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]octo-2-ene-2-carboxylate (3a)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 12.5 g of diphenylmethyl (6R,7R)-7-phenylacetamide-3-hydroxy-8-oxo-5-thia-1-azabicyclo[4.2.0]octo-2-ene-2-carboxylate(2a) (purity: 90%, 22.5 millimole) and 70 ml of dehydrateddiethylformamide was then added thereto and dissolved with stirring atroom temperature. To this solution, the diethylformamide solution ofdiethyl chloroiminium chloride compound in Preparation Example 6 wasadded with ice cooling. After the reaction mixture was further stirredat room temperature for 6 hours, it was poured into 1 liter of icewater. The separated crystal was filtered and then washed with a smallamount of water, followed by vacuum drying to prepare 11.9 g of thedesired compound (3a) (purity: 94% yield: 96%).

¹H NMR(DMSO) δppm 3.52 (ABq., 2H, J=12 Hz), 3.96 (ABq., 2H, J=15 Hz),5.21 (d, 1H, 5.5 Hz), 5.78 (dd, 1H, 7.5 Hz, 5.5 Hz), 6.97 (s, 1H),7.18˜7.49 (m, 15H), 9.20 (d, 1H, 7.5 Hz)

Example 2

Preparation of Compound (3a)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 12.5 g of Compound (2a) (purity:90%, 22.5 millimole) and 70 ml of dehydrated dimethylformamide was thenadded thereto and dissolved with stirring at room temperature. To thissolution, the dimethylformamide solution of dimethyl chloroiminiumchloride compound in Preparation Example 7 and 118 mg (5 mole %) ofdimethyl sulfone were added with ice cooling. The reaction mixture wastreated in the same manner as in Example 1, to prepare 11.5 g of thedesired compound (3a) (purity: 95%, yield: 94%). This was identical withExample 1 in ¹H NMR(DMSO) spectrum.

Example 3

Preparation of p-methoxybenzyl(6R, 7R)-7-phenylacetamide-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]octo-2-ene -2-carboxylate (3b)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 11.4 g of p-methoxybenzyl (6R,7R)-7-phenylacetamide-3-hydroxy-8-oxo-5-thia-1-azabicyclo[4.2.0]octo-2-ene-2-carboxylate(2b) (purity: 92%, 23.1 millimole) and 70 ml of dehydrateddiethylformamide was then added thereto and dissolved with stirring atroom temperature. To this solution, the diethylformamide solution ofdiethylchloroiminium chloride compound in Preparation Example 6 wasadded with ice cooling. The reaction mixture was treated in the samemanner as in Example 1, to prepare 11.0 g of the desired compound (3b)(purity: 96%, yield: 97%).

¹H NMR(CDCl₃) δppm 3.42 (d, 1H, J=17.8 Hz), 3.72 (d, 1H, J=17.8 Hz),3.58 (d, 1H, J=16.4 Hz), 3.64 (d, 1H, J=16.4 Hz), 3.79 (s, 3H), 4.96 (d,1H, 5.1 Hz), 5.21 (s, 2H), 5.79 (dd, 1H, 9.2 Hz, 5.1 Hz), 6.39 (d, 1H,9.2 Hz), 6.82˜7.40 (m, 9H)

Example 4

Preparation of Compound (3b)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 11.4 g of Compound (2b) (purity:92%, 23.1 millimole) and 70 ml of dehydrated dimethylformamide was thenadded with stirring at room temperature. To this solution, thedimethylformamide solution of dimethyl chloroiminium chloride compoundin Preparation Example 7 and 118 mg (5 mole %) of dimethyl sulfone wereadded with ice cooling. The reaction mixture was treated in the samemanner as in Example 1, to prepare 10.8 g of the desired compound (3b)(purity: 96%, yield: 95%). This was identical with Example 3 in ¹HNMR(CDCl₃) spectrum.

Example 5

Preparation of diphenylmethyl (6R,7R)-7-phthalimide-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]octo-2-ene-2-carboxylate(3c)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 12.7 g of diphenylmethyl (6R,7R)-7-phthalimide-3-hydroxy-8-oxo-5-thia-1-azabicyclo[4.2.0]octo-2-ene-2-carboxylate(2c) (purity: 95%, 23.8 millimole) and 70 ml of dehydrateddiethylformamide was then added thereto and dissolved with stirring atroom temperature. To this solution, the diethylformamide solution ofdiethyl chloroiminium chloride compound in Preparation Example 6 wasadded with ice cooling. The reaction mixture was treated in the samemanner as in Example 1, to prepare 12.5 g of the desired compound (3c)(purity: 93%, yield: 92%).

¹H NMR(CDCl₃) δ4.19˜4.90 (m, 2H), 4.625 (ABq., 2H, J=5.5 Hz), 5.975 (d,1H, J=4.8 Hz), 6.970 (s, 1H), 7.21˜7.62 (m, 10H), 7.76˜7.94 (m, 4H)

Example 6

Preparation of Compound (3c)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 12.7 g of Compound (2c) (purity:95%, 23.8 millimole) and 70 ml of dehydrated dimethylformamide was thenadded thereto and dissolved with stirring at room temperature. To thissolution, the dimethylformamide solution of dimethyl chloroiminiumchloride compound in Preparation Example 7 and 118 mg (5 mole %) ofdimethyl sulfone were added with ice cooling. The reaction mixture wastreated in the same manner as in Example 1, to prepare 13.1 g of thedesired compound (3c) (purity: 90%, yield: 93%). This was identical withExample 5 in ¹H NMR (CDCl₃) spectrum.

Example 7

Preparation of Compound (3a)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 12.5 g of Compound (2a) (purity:90%, 22.5 millimole) and 70 ml of dehydrated dimethylformamide was thenadded thereto and dissolved with stirring at room temperature. To thissolution, the diethylformamide solution of diethyl chloroiminiumchloride compound in Preparation Example 6 and 118 mg (5 mole %) ofdimethyl sulfone were added with ice cooling. The reaction mixture wastreated in the same manner as in Example 1, to prepare 12.2 g of thedesired compound (3a) (purity: 92%, yield: 96%). This was identical withExample 1 in ¹H NMR(DMSO) spectrum.

Example 8

Preparation of Compound (3a)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 12.5 g of Compound (2a) (purity:90%, 22.5 millimole) and 70 ml of dehydrated dimethylformamide was thenadded thereto and dissolved with stirring at room temperature. To thissolution, the dimethylformamide solution of dimethyl chloroiminiumchloride compound in Preparation Example 7 and 154 mg (5 millimole %) ofdiethyl sulfone were added with ice cooling. The reaction mixture wastreated in the same manner as in Example 1, to prepare 11.6 g of thedesired compound (3a) (purity: 95%, yield: 95%). This was identical withExample 1 in ¹H NMR(DMS0) spectrum.

Example 9

Preparation of Compound (3a)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 12.5 g of Compound (2a) (purity:90%, 22.5 millimole) and 70 ml of dehydrated dimethylformamide was thenadded thereto and dissolved with stirring at room temperature. To thissolution, the dimethylformamide solution of dimethyl chloroiminiumchloride compound in Preparation Example 7 and 274 mg (5 mole %) ofdiphenyl sulfone were added with ice cooling. The reaction mixture wastreated in the same manner as in Example 1, to prepare 11.8 g of thedesired compound (3a) (purity: 90%, yield: 91%). This was identical withExample 1 in ¹H NMR(DMSO) spectrum.

Example 10

Preparation of N-[(benzyloxy) carbonyl]-4-chloro-2-cyclohexyl-1,2-dihydropyridine (3d)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 7.2 g (23 millimole) ofN-[(benzyloxy)carbonyl]-2-cyclohexyl-2,3-dihydro-4-pyridone (2d) and 70ml of dehydrated diethylformamide was then added thereto and dissolvedwith stirring at room temperature. To this solution, thediethylformamide solution of diethyl chloroiminium chloride compound inPreparation Example 6 was added with ice cooling. The reaction mixturewas further stirred at room temperature for 6 hours, and this was pouredinto 1 liter of ice water and then extracted with 50 ml of ethylacetate. After drying with anhydrous magnesium sulfate, this wassubjected to concentration at reduced pressure and then purified withsilicagel column chromatography, to prepare 7.7 g of the desiredcompound (3d) (purity: 97%, yield: 98%), as a colorless transparent oil.This was identical with standard sample in ¹H NMR(CDCl₃) spectrum.

Example 11

Preparation of Compound (3d)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 7.2 g of Compound (2d) (23millimole) and 70 ml of dehydrated dimethylformamide was then addedthereto and dissolved with stirring at room temperature. To thissolution, the dimethylformamide solution of dimethyl chloroiminiumchloride compound in Preparation Example 7 and 118 mg (5 mole %) ofdimethyl sulfone were added with ice cooling. The reaction mixture wastreated in the same manner as in Example 10, to prepare 7.6 g of thedesired compound (3d) (purity: 96%, yield: 96%), as a colorlesstransparent oil. This was identical with standard sample in ¹HNMR(CDCl₃) spectrum.

Example 12

Preparation of 2-chloro-5-tert-butyl-1,3-dinitrobenzene (3e)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 5.5 g (23 millimole) of4-tert-butyl-2,6-dinitrophenol (2e) and 70 ml of dehydrateddiethylformamide was then added thereto and dissolved with stirring atroom temperature. To this solution, the diethylformamide solution ofdiethyl chloroiminium chloride compound in Preparation Example 6 wasadded with ice cooling. After the reaction mixture was further stirredat room temperature for 6 hours, it was poured into 1 liter of icewater. The separated crystal was filtered and then washed with a smallamount of cooled methanol, followed by vacuum drying to prepare 6.1 g ofthe desired compound (3e) (purity: 95%, yield: 97%). Its melting point(113 to 115° C.) was similar to that of standard sample (115° C.).

Example 13

Preparation of Compound (3e):

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 5.5 g of Compound (2e) (23millimole) and 70 ml of dehydrated dimethylformamide was then addedthereto and dissolved with stirring at room temperature. To thissolution, the dimethylformamide solution of dimethyl chloroiminiumchloride compound in Preparation Example 7 and 118 mg (5 mole %) ofdimethyl sulfone were added with ice cooling. The reaction mixture wastreated in the same manner as in Example 12, to prepare 6.0 g of thedesired compound (3e) (purity: 92%, yield: 92%). This was identical withstandard sample in melting point and elementary analysis.

Example 14

Preparation of 3-α-chlorocholestane (3f)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 8.9 g (23 millimole) of3-β-cholestanol (2f) and 70 ml of dehydrated dimethylformamide was thenadded thereto and dissolved with stirring at room temperature. To thissolution, the diethylformamide solution of diethyl chloroiminiumchloride compound in Preparation Example 6 was added with ice cooling.The reaction mixture was treated in the same manner as in Example 1, toprepare 9.5 g of the desired compound (3f) (purity: 90%, yield: 91%).Its melting point (105 to 106° C. was similar to that of standard sample(104° C.).

Example 15

Preparation of Compound (3f)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 8.9 g (23 millimole) of Compound(2f) and 70 ml of dehydrated dimethylformamide was then added theretoand dissolved with stirring at room temperature. To this solution, thedimethylformamide solution of dimethyl chloroiminium chloride compoundin Preparation Example 7 and 118 mg (5 mole %) of dimethyl sulfone wereadded with ice cooling. The reaction mixture was treated in the samemanner as in Example 1, to prepare 9.6 g of the desired compound (3f)(purity: 93%, yield: 95%) This was identical with standard sample inmelting point and elementary analysis.

Example 16

Preparation of 4,4-ethylenedioxypentane-1-chloride (3g)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 3.4 g (23 millimole) of4,4-ethylenedioxypentane-1-ol (2g) and 70 ml of dehydrateddimethylformamide was then added thereto and dissolved with stirring atroom temperature. To this solution, the diethylformamide solution ofdiethyl chloroiminium chloride compound in Preparation Example 6 wasadded with ice cooling. The reaction mixture was treated in the samemanner as in Example 10, to prepare 3.9 g of the desired compound (3g)(purity: 96%, yield: 98%), as a colorless transparent oil. This wasidentical with standard sample in ¹H NMR(CDCl₃) spectrum.

Example 17

Preparation of Compound (3g)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 3.4 g (23 millimole) of Compound(2 g) and 70 ml of dehydrated dimethylformamide was then added theretoand dissolved with stirring at room temperature. To this solution, thedimethylformamide solution of dimethyl chloroiminium chloride compoundin Preparation Example 7 and 118 mg (5 mole %) of dimethyl sulfone werethen added with ice cooling. The reaction mixture was treated in thesame manner as in Example 10, to prepare 3.8 g of the desired compound(3g) (purity: 94 %, yield: 95%), as a colorless transparent oil. Thiswas identical with standard sample in ¹H NMR(CDCl₃) spectrum. Examples18 to 30

The halogenating reaction was conducted in the same manner as in Example1 except for the use of a starting material shown below and achlorinating agent shown in Table 1, and the employment of reactionconditions shown in Table 2, to prepare the desired halogenide.

Starting material I

II n-C₁₁H₂₃OH III

IV

V

VI

VII

VIII

IX

X

XI

XII

XIII

Halogenating agent 1a

1c

1d

1f

1g

Starting Reaction Halogenating Ex. material Solvent condition agent 18(I) dichloromethane RT × 3 hr (1f) 19 (II) chloroform RT × 5 hr (1c) 20(III) chloroform RT × 5 hr (1g) 21 (IV) dichloromethane RT × 5 hr (1a)22 (V) dichloromethane RT × 5 hr (1a) 23 (VI) dichloromethane RT × 5 hr(1a) 24 (VII) tetrahydrofuran RT × 3 hr (1d) 25 (VIII) tetrahydrofuranRT × 3 hr (1d) 26 (IX) diethylformamide RT × 6 hr (1a) 27 (X) trichlene RT × 10 hr (1a) 28 (XI) dimethylimidazolidinone RT × 7 hr (1a) 29 (XI)N-methyl-pyrrolidone RT × 7 hr (1a) 30 (XII) tetrahydrofuran RT × 6 hr(1a) Prod- uct Exam- ple 18

19 n-C₁₁H₂₃Cl 20

21

22

23

24

25

26

27

28

29

30

RT: Room temperature

Comparative Example 1

Preparation of Compound (3a)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 12.5 g of Compound (2a) (purity:90%, 22.5 millimole) and 70 ml of dehydrated diethylformamide was thenadded thereto and dissolved with stirring at room temperature. To thissolution, the dimethylformamide solution of dimethyl chloroiminiumchloride compound in Preparation Example 7 was added with ice cooling.

After the reaction mixture was further stirred at room temperature for24 hours, it was poured into 1 liter of ice water. The separated crystalwas filtered and then washed with a small amount of water, followed byvacuum drying to prepare 12.1 g of the desired compound (3a) (purity:80%, yield: 83%). This was identical with Example 1 in ¹H NMR(DMSO)spectrum.

Comparative Example 2

Preparation of Compound (3b)

Into a 300-ml four-necked flask equipped with a thermometer, a calciumchloride tube and a stirrer was placed 11.4 g of Compound (2b) (purity:92%, 23.1 millimole) and 70 ml of dehydrated diethylformamide was thenadded thereto and dissolved with stirring at room temperature. To thissolution, the dimethylformamide solution of dimethyl chloroiminiumchloride compound in Preparation Example 7 was added with ice cooling.

The reaction mixture was treated in the same manner as in ComparativeExample 2, to prepare 10.7 g of the desired compound (3b) (purity: 81%,yield: 80%). This was identical with Example 3 in ¹H NMR(CDCl₃)spectrum.

INDUSTRIAL APPLICABILITY

In accordance with the invention, it is possible to overcome thedrawbacks of long reaction time, unstable yield, low purity, and theformation of by-product obtained by halogenation of other than thedesired hydroxyl group, which drawbacks being common to the methods ofhalogenating hydroxyl group by using dimethyl haloiminium compound ordiphenyl haloiminium compound.

What is claimed is:
 1. A method of halogenating a hydroxyl groupcomprising reacting in an organic solvent at least one halogenatingagent selected from the group consisting of a halogenating agent of theformula (1) and a halogenating agent of the formula (4), and at leastone compound selected from the group consisting of lower alkyl sulfone,lower alkenyl sulfone, aryl sulfone and heterocyclic sulfone at the sametime, with a hydroxyl group containing compound of the formula (2) toobtain a halogenide of the formula (3)

wherein R¹ and R² are the same or different and are each ethyl, propyl,isopropyl, butyl, isobutyl or allyl; X is chlorine atom or bromine atom;and Y is chlorine ion, bromine ion, dichlorophosphate ion,dibromophosphate ion, chlorosulfonate ion, bromosulfonate ion,chlorooxalate ion or bromooxalate ion; A-OH  (2) wherein A is astraight-chain or branched-chain alkyl group which may be substituted, astraight-chain or branched-chain alkenyl group which may be substituted,a monocyclic or polycyclic aromatic residue which may be substituted, asteroid residue, or a monocyclic or polycyclic heterocyclic residuewhich may be substituted; A-X  (3) wherein A and X are the same asabove;

wherein R¹ and R⁴ are methyl or phenyl; and X and Y are the same asabove.
 2. A method of halogenating a hydroxyl group as defined in claim1 wherein the hydroxyl group containing compound (2) is at least oneselected from the group consisting of compounds (5) through (11):compound (5): straight-chain or branched-chain alkyl alcohol in whichthe alkyl part has 1 to 15 carbon atoms and may be substituted, compound(6): straight-chain or branched-chain alkenyl alcohol in which alkenylpart has 2 to 8 carbon atoms and may be substituted, compound (7):3β-cholesterol, compound (8): compounds of the formula (8):

 wherein R⁵ to R⁸ are the same or different and are each hydrogen atom,C₁-C₄ lower alkyl group, nitro group, hydroxyl group, carboxyl group, orsubstituted oxycarbonyl group, compound (9): compounds of the formulas(9a) to (9c):

 wherein R⁹ is a straight-chain or branched-chain C₁-C₁₅, alkyl group, astraight-chain or branched-chain C₂-C₈ alkenyl group, cyclohexyl group,or phenyl group; and R^(a) is hydrogen atom or a substituted oxycarbonylgroup, compound (10): compounds of the formula (10):

 wherein R¹⁰ is hydrogen atom, amino group, or a protected amino group;R¹¹ is hydrogen atom or lower alkoxy group; or, alternatively, R¹⁰ andR¹¹ may be bonded with each other to form a cyclic amino protectinggroup; and R¹² is hydrogen atom or carboxylic acid protecting group, andcompound (11): compounds of the formula (11):

 wherein R¹³ to R¹⁶ are the same or different and are each hydrogenatom, C₁-C₄, lower alkyl group, nitro group, hydroxyl group, carboxylgroup, or a substituted oxycarbonyl group; and n is 1 or
 2. 3. A methodof halogenating a hydroxyl group as defined in claim 2 wherein thehydroxyl group containing compound (2) is at least one selected from thegroup consisting of the compounds (5) through (10).
 4. A method ofhalogenating a hydroxyl group as defined in claim 3 wherein the hydroxylgroup containing compound (2) is at least one selected from the groupconsisting of the compounds (7) to (10).
 5. A method of halogenating ahydroxyl group as defined in claim 4 wherein the hydroxyl groupcontaining compound (2) is at least one selected from the groupconsisting of the compounds (9) and (10).
 6. A method of halogenating ahydroxyl group as defined in claim 6 wherein the hydroxyl groupcontaining compound (2) is compound (10).